PMID- 26542378
OWN - NLM
STAT- MEDLINE
DCOM- 20160614
LR  - 20210202
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 127
IP  - 4
DP  - 2016 Jan 28
TI  - A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed 
      and refractory mature B-cell malignancies.
PG  - 411-9
LID - 10.1182/blood-2015-08-664086 [doi]
AB  - We report the results of a multicenter phase 1 dose-escalation study of the 
      selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with 
      relapsed/refractory B-cell malignancies. There were 9 dose-escalation cohorts 
      ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 
      300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients 
      (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 
      CLL patients remain on treatment. Lymph node responses were rapid and associated 
      with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell 
      lymphoma (92%) responded (median treatment duration, 40 weeks). Eleven of 31 
      non-germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded 
      but median treatment duration was 12 weeks due to development of progressive 
      disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) 
      being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. 
      Grade 3/4 AEs were mainly hematologic and recovered spontaneously during therapy. 
      One CLL patient experienced a grade 3 treatment-related bleeding event 
      (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac 
      dysrhythmias, or arthralgia were observed. No maximal tolerated dose (MTD) was 
      reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients 
      developed a dose-limiting toxicity, yielding an MTD of 480 mg once daily. 
      ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies 
      without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer 
      advantages in combination therapies. This trial was registered at 
      www.clinicaltrials.gov as #NCT01659255.
CI  - (c) 2016 by The American Society of Hematology.
FAU - Walter, Harriet S
AU  - Walter HS
AUID- ORCID: 0000-0003-2618-711X
AD  - Ernest and Helen Scott Haematological Research Institute, University of 
      Leicester, Leicester, United Kingdom;
FAU - Rule, Simon A
AU  - Rule SA
AD  - Department of Haematology, Plymouth Hospitals NHS Trust, Plymouth, United 
      Kingdom;
FAU - Dyer, Martin J S
AU  - Dyer MJ
AUID- ORCID: 0000-0002-5033-2236
AD  - Ernest and Helen Scott Haematological Research Institute, University of 
      Leicester, Leicester, United Kingdom;
FAU - Karlin, Lionel
AU  - Karlin L
AD  - Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Service d'Hematologie, 
      Pierre-Benite, Universite Claude Bernard Lyon 1, Lyon, France;
FAU - Jones, Ceri
AU  - Jones C
AD  - Cardiff CLL Research Group, School of Medicine, Heath Park, Cardiff, Wales, 
      United Kingdom;
FAU - Cazin, Bruno
AU  - Cazin B
AD  - Department of Clinical Hematology, Centre Hospitalier Regional Universitaire 
      (CHRU) de Lille, and Unite Groupe de Recherche sur les Formes Injectables et les 
      Technologies Associees (GRITA), Universite de Lille 2, Lille, France;
FAU - Quittet, Philippe
AU  - Quittet P
AD  - Department of Clinical Hematology and Unite Mixte de Recherche (UMR)-Centre 
      National de la Recherche Scientifique (CNRS) 5235, CHRU, Montpellier, France;
FAU - Shah, Nimish
AU  - Shah N
AD  - Department of Haematology, Plymouth Hospitals NHS Trust, Plymouth, United 
      Kingdom;
FAU - Hutchinson, Claire V
AU  - Hutchinson CV
AD  - Ernest and Helen Scott Haematological Research Institute, University of 
      Leicester, Leicester, United Kingdom; Department of Haematology, Plymouth 
      Hospitals NHS Trust, Plymouth, United Kingdom;
FAU - Honda, Hideyuki
AU  - Honda H
AD  - ONO Pharmaceuticals Co Ltd, Osaka, Japan; and.
FAU - Duffy, Kevin
AU  - Duffy K
AD  - ONO Pharma UK Ltd, London, United Kingdom.
FAU - Birkett, Joseph
AU  - Birkett J
AD  - ONO Pharma UK Ltd, London, United Kingdom.
FAU - Jamieson, Virginia
AU  - Jamieson V
AD  - ONO Pharma UK Ltd, London, United Kingdom.
FAU - Courtenay-Luck, Nigel
AU  - Courtenay-Luck N
AD  - ONO Pharma UK Ltd, London, United Kingdom.
FAU - Yoshizawa, Toshio
AU  - Yoshizawa T
AD  - ONO Pharmaceuticals Co Ltd, Osaka, Japan; and.
FAU - Sharpe, John
AU  - Sharpe J
AD  - ONO Pharma UK Ltd, London, United Kingdom.
FAU - Ohno, Tomoya
AU  - Ohno T
AD  - ONO Pharmaceuticals Co Ltd, Osaka, Japan; and.
FAU - Abe, Shinichiro
AU  - Abe S
AD  - ONO Pharma UK Ltd, London, United Kingdom.
FAU - Nishimura, Akihisa
AU  - Nishimura A
AD  - ONO Pharmaceuticals Co Ltd, Osaka, Japan; and.
FAU - Cartron, Guillaume
AU  - Cartron G
AD  - Department of Clinical Hematology and Unite Mixte de Recherche (UMR)-Centre 
      National de la Recherche Scientifique (CNRS) 5235, CHRU, Montpellier, France;
FAU - Morschhauser, Franck
AU  - Morschhauser F
AD  - Department of Clinical Hematology, Centre Hospitalier Regional Universitaire 
      (CHRU) de Lille, and Unite Groupe de Recherche sur les Formes Injectables et les 
      Technologies Associees (GRITA), Universite de Lille 2, Lille, France;
FAU - Fegan, Christopher
AU  - Fegan C
AD  - Cardiff CLL Research Group, School of Medicine, Heath Park, Cardiff, Wales, 
      United Kingdom;
FAU - Salles, Gilles
AU  - Salles G
AUID- ORCID: 0000-0002-9541-8666
AD  - Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Service d'Hematologie, 
      Pierre-Benite, Universite Claude Bernard Lyon 1, Lyon, France;
LA  - eng
SI  - ClinicalTrials.gov/NCT01659255
GR  - C325/A15575/Cancer Research UK/United Kingdom
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20151105
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Imidazoles)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrimidines)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (Agammaglobulinaemia Tyrosine Kinase)
RN  - EC 2.7.10.2 (BTK protein, human)
RN  - LXG44NDL2T (tirabrutinib)
SB  - IM
MH  - Adult
MH  - Agammaglobulinaemia Tyrosine Kinase
MH  - Aged
MH  - Aged, 80 and over
MH  - B-Lymphocytes/*drug effects/pathology
MH  - Cohort Studies
MH  - Female
MH  - Humans
MH  - Imidazoles/adverse effects/blood/*therapeutic use
MH  - Leukemia, Lymphocytic, Chronic, B-Cell/*drug therapy/pathology
MH  - Lymphoma, Large B-Cell, Diffuse/*drug therapy/pathology
MH  - Lymphoma, Mantle-Cell/*drug therapy/pathology
MH  - Male
MH  - Middle Aged
MH  - Neoplasm Recurrence, Local/drug therapy/pathology
MH  - Protein Kinase Inhibitors/adverse effects/blood/*therapeutic use
MH  - Protein-Tyrosine Kinases/*antagonists & inhibitors
MH  - Pyrimidines/adverse effects/blood/*therapeutic use
PMC - PMC4731845
EDAT- 2015/11/07 06:00
MHDA- 2016/06/15 06:00
PMCR- 2016/01/28
CRDT- 2015/11/07 06:00
PHST- 2015/08/12 00:00 [received]
PHST- 2015/10/22 00:00 [accepted]
PHST- 2015/11/07 06:00 [entrez]
PHST- 2015/11/07 06:00 [pubmed]
PHST- 2016/06/15 06:00 [medline]
PHST- 2016/01/28 00:00 [pmc-release]
AID - S0006-4971(20)30514-0 [pii]
AID - 2015/664086 [pii]
AID - 10.1182/blood-2015-08-664086 [doi]
PST - ppublish
SO  - Blood. 2016 Jan 28;127(4):411-9. doi: 10.1182/blood-2015-08-664086. Epub 2015 Nov 
      5.